The rat with transplantable Walker 256 carcinoma (T) with decreased serum T4 and T3 but normalserum TSH and liver alpha-glycerophosphate dehydrogenase (alpha-GPD) activity will be studied further as a model for patients with nonthyroidal disease who have decreased serum T3. We propose to determine whether the described decrease in nuclear T3 receptors reflects a specific or general change in nonhistone protein synthesis, whether other aspects of protein synthesis are altered in T rats and whether pituitary nuclear T3 receptors and growth hormone (GH) content are changed in these animals. We also propose to define the T3 dose response curves for liver alpha-GPD, malic enzyme (ME) and pituitary GH and to develop an in vitro model where tumor products may reproduce, in cultured cells, the effects observed in intact animal bearing tumors. In this in vitro system we hope to define the chemical nature of tumor products that effect the nuclear T3 receptor and thyroid hormone action. We have previously shown that infants of diabetic mothers have decreased serum T3 during the first three days of life compared to infants of nondiabetic mothers of comparable gestational age. We now hope to develop a rat model (streptozotocin) of perinatal diabetes mellitus to define the ontogeny of thyroid function and biological effects, specifically liver alpha-GPD, glucuronyl transferase and lung lecithin content. We will characterize the model in the neonatal state as well. Initial studies suggest that 5,5'-diphenylhydantoin (DPH) inhibits TSH secretion, decreases specific nuclear binding of T3, and increases hepatic ME and pituitary GH. We now propose to determine the dose repsonse relationship between T3 and pituitary TSH and GH secretion in intactrats and cultured anterior pituitary cells. We will also define whether DPH effects on hormone secretion require protein or RNA synthesis. We will further determine whether the drug interacts directly with T3 at the receptor. The inhibition of T3-induced changes in ME and GH is of particular interest and this will be characterized by determining their appropriate dose response curves. We will determine whether the above changes reflect new protein synthesis resulting from altered gene regulation. If so, we will determine whether DPH or analogues to be developed may be useful in the management of thyrotoxicosis.